Azabicyclylmethyl derivatives of 7,8-dihydro-1,6,9,-trioxa-3-aza-cyclopenta[a]naphthalene as 5-ht1a antagonists

ABSTRACT

Compounds of the formula  
                 
are useful for treating the cognitive deficits due to aging, stroke, head trauma, Alzheimer&#39;s disease or other neurodegenerative diseases, or schizophrenia and are also useful for the treatment of disorders such as anxiety, aggression and stress, and for the control of various physiological phenomena, such eating disorders, disorders of thermoregulation, and sleep and sexual dysfunction.

BACKGROUND OF THE INVENTION

This application claims priority from co-pending provisional applicationSer. No. 60/286,818, filed on Apr. 26, 2001, the entire disclosure ofwhich is hereby incorporated by reference.

Recent studies with the selective 5-HT_(1A) antagonist WAY-100635 haveconfirmed a role for 5-HT_(1A) receptors in learning and memory. Carliet. al. (Neuropharmacology (1999), 38(8), 1165-1173) demonstrated thatWAY-100635 prevented the impairment of spatial learning caused byintrahippocampal injection of3-[(R)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP), acompetitive NMDA receptor antagonist, in a two-platform spatialdiscrimination task. Boast et. al. (Neurobiol. Learn. Mem. (1999), 71(3)259-271) found that WAY-100635 significantly reduced the cognitiveimpairment induced by the non-competitive NMDA antagonist MK801, asdetermined by the performance of rats trained on a delayed nonmatchingto sample radial arm maze task. Menesis et. al. (Neurobiol. Learn. Mem.(1999), 71(2) 207-218) showed that post-training administration ofWAY-100635 reversed the learning deficit induced by scopolamine, acholinergic antagonist, in an autoshaping learning task. New and novel5-HT_(1A) antagonists would be useful for these and other uses.

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a group of novel5-HT_(1A) antagonists of the formula I:

wherein

R¹ is hydrogen, halo, cyano, carboxamido, carboalkoxy of two to sixcarbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- ordialkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms;

X-Y-Z is N═C(R²)—O, N═C(R²)—NH or NH—C(R²)═CH;

R² is hydrogen, halo, trifluoromethyl, amino, mono- or di-alkylamino inwhich each alkyl group has 1 to 6 carbon atoms, alkoxy of one to sixcarbon atoms or alkyl of one to six carbon atoms; and

R³ is phenyl, naphthyl, anthracyl, phenanthryl, pyridyl, pyrimidyl,triazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, indolyl, imidazolyl,benzofuryl, benzothienyl, oxazolyl, or thiazolyl, each optionallysubstituted with from one to three substituents selected from hydroxy,halo, trifluoromethyl, cyano, amino, mono- or di-alkylamino in whicheach alkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbonatoms and alkyl of one to six carbon atoms;

or a pharmaceutically acceptable salt thereof.

In some embodiments of the present invention X-Y-Z is N═C(R²)—O.

R¹ is preferably hydrogen, halo, trifluoromethyl, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, amino, mono- or di-alkylamino inwhich each alkyl group has 1 to 6 carbon atoms. In more preferredembodiments, R¹ is hydrogen, trifluoromethyl, alkyl of one to six carbonatoms or alkoxy of one to six carbon atoms.

In some embodiments of the present invention R² is preferably hydrogen,trifluoromethyl, amino, mono- or dialkylamino in which each alkyl grouphas one to six carbon atoms, or alkyl of 1 to 6 carbon atoms, R² is morepreferably hydrogen, trifluoromethyl, or alkyl of one to six carbonatoms. R² is still more preferably hydrogen or alkyl of one to sixcarbon atoms and still more preferably alkyl from 1 to 3 carbon atoms.

In other embodiments of -the present invention R³ is phenyl, naphthyl,pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, pyrazolyl, indolyl,imidazolyl, benzofuryl, or benzothienyl, each optionally substitutedwith from one to three substituents selected from hydroxy, halo,trifluoromethyl, cyano, amino, mono- or di-alkylamino in which eachalkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atomsand alkyl of one to six carbon atoms. R3 is more preferably phenyl,naphthyl, pyridyl, pyrrolyl, indolyl, or benzothienyl, each optionallysubstituted with from one to three substituents selected from halo,trifluoromethyl, cyano, alkoxy of one to six carbon atoms and alkyl ofone to six carbon atoms R³ is preferably phenyl or naphthyl, eachoptionally substituted with from one to three substituents selected fromhalo, trifluoromethyl, cyano, alkoxy of one to six carbon atoms andalkyl of one to six carbon atoms.

Still more preferred compounds are those in which R¹ is hydrogen, halo,trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to sixcarbon atoms, amino, mono- or di-alkylamino in which each alkyl grouphas one to six carbon atoms; R² is hydrogen, trifluoromethyl, amino,mono- or di-alkylamino in which each alkyl group has one to six carbonatoms, or alkyl of one to six carbon atom; and R³ is phenyl, naphthyl,pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, pyrazolyl, indolyl,imidazolyl, benzofuryl, or benzothienyl, each optionally substitutedwith from one to three substituents selected from hydroxy, halo,trifluoromethyl, cyano, amino, mono- or di-alkylamino in which eachalkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atomsand alkyl of one to six carbon atoms.

Most preferred are those in which R¹ is hydrogen, halo, trifluoromethyl,alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms;R² is hydrogen, trifluoromethyl or alkyl of one to six carbon atom; andR³ is phenyl, naphthyl, pyridyl, pyrrolyl, indolyl, or benzothienyl,each optionally substituted with from one to three substituents selectedfrom halo, trifluoromethyl, cyano, alkoxy of one to six carbon atoms andalkyl of one to six carbon atoms.

This invention relates to both the R and S stereoisomers of the8-aminomethyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene,as well as to mixtures of the R and S stereoisomers. Throughout thisapplication, the name of the product of this invention, where theabsolute configuration of the8-aminomethyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene isnot indicated, is intended to embrace the individual R and S enantiomersas well as mixtures of the two. In some preferred embodiments of thepresent invention the S isomer is preferred.

Where a stereoisomer is preferred, it may, in some embodiments beprovided substantially free of the corresponding enantiomer. Thus, anenantiomer substantially free of the corresponding enantiomer refers toa compound which is isolated or separated via separation techniques orprepared free of the corresponding enantiomer. Substantially free, asused herein means that the compound is made up of a significantlygreater proportion of one stereoisomer. In preferred embodiments thecompound is made up of at least about 90% by weight of a preferredstereoisomer. In other embodiments of the invention, the compound ismade up of at least about 99% by weight of a preferred stereoisomer.Preferred stereoisomers may be isolated from racemic mixtures by anymethod known to those skilled in the art, including high performanceliquid chromatography (HPLC) and the formation and crystallization ofchiral salts or by methods described herein. See, for example, Jacques,et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, NewYork, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen,S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

Alkyl as used herein refers to an aliphatic hydrocarbon chain andincludes straight and branched chains such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1to 3 carbon atoms.

Alkanamido as used herein refers to the group R—C(═O)—NH— where R is analkyl group of 1 to 5 carbon atoms.

Alkanoyloxy as used herein refers to the group R—C(═O)—O— where R is analkyl group of 1 to 5 carbon atoms.

Alkanesulfonamido as used herein refers to the group R—S(O)₂—NH— where Ris an alkyl group of 1 to 6 carbon atoms.

Alkoxy as used herein refers to the group R—O— where R is an alkyl groupof 1 to 6 carbon atoms.

Carboxamido, as used herein refers to the group —CO—NH₂.

Carboalkoxy as used herein refers to the group R—O—C(═O)— where R is analkyl group of 1 to 5 carbon atoms.

Halogen (or halo) as used herein refers to chlorine, bromine, fluorineand iodine.

Pharmaceutically acceptable salts are those derived from such organicand inorganic acids as: acetic, lactic, citric, cinnamic, tartaric,succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic,pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic,benzoic, and similarly known acceptable acids.

Specific compounds of Formula I include:

-   8-{[2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl}-3-phenyl-8-azabicyclo[3.2.    1 ]octan-3-ol;-   8-([2-Methyl-7,8-dihydro[1 ,4]dioxino[2,3-g][1    ,3]benzoxazol-8-yl]methyl}-3-[3-(trifluoromethyl)phenyl]-8-azabicyclo[3.2.    1 ]octan-3-ol;-   8-{[2-Methyl-7,8-dihydro[1 ,4]dioxino[2,3-g][1    ,3]benzoxazol-8-yl]methyl}-3-(2-naphthyl)-8-azabicyclo[3.2. 1    ]octan-3-ol.

Compounds of the present invention are prepared in accordance with thefollowing schemes and specific examples. Variables used are as definedfor Formula I unless otherwise noted.

The8-azabicyclylmethyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta-[a]-naphthalenesof the invention are prepared as illustrated in Scheme I, below.Specifically, the appropriately substituted nitroguaiacol is alkylatedwith allyl bromide in the presence of a suitable base such as sodiumhydride and then demethylated by a reagent such as sodium hydroxide. Theresulting 4-nitro-2-allyloxyphenol is then alkylated with glycidyltosylate or an epihalohydrin in the presence of a base such as sodiumhydride and heated in a high boiling solvent such as mesitylene orxylene to effect both rearrangement of the allyl group and cyclizationof the dioxan ring. The resulting primary alcohol is converted to thetosylate by reaction with p-toluenesulfonyl chloride in the presence ofa tertiary amine or pyridine or alternatively to a halide by reactionwith carbon tetrabromide or carbon tetrachloride in combination withtriphenylphosphine. The allyl side chain is then isomerized by treatmentwith catalytic bis-acetonitrile

palladium (II) chloride in refluxing methylene chloride or benzene andthe nitro group reduced to the aniline with a suitable reducing agentsuch as tin (II) chloride. The aniline is then acylated with theappropriate acyl halide or anhydride and the olefin cleaved to thecorresponding o-amidobenzaldehyde by treatment with catalytic osmiumtetroxide in the presence of sodium periodate. The aldehyde is convertedto the phenol by treatment with meta-chloroperoxybenzoic acid in aBaeyer-Villager reaction and cyclization to the7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene is effected bytreatment at reflux with an appropriate dehydrating agent such as anortho ester. Replacement of the tosylate or halide with theappropriately substituted azabicycle in some high boiling solvent suchas dimethyl sulfoxide gives the title compounds of the invention.

Alternatively, as shown in Scheme II, the aniline produced by the tin(II) chloride reduction described above may be protected by a suitableprotecting group such as carbobenzoxy (Cbz) before the olefin is cleavedto the aldehyde by treatment with osmium tetroxide/sodium periodate andthe aldehyde converted to a phenol by the Baeyer-Villager procedure.Deprotection by treatment with hydrogen over palladium on carbon givesthe o-aminophenol, which is cyclized to the7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene by treatmentwith the appropriate ortho ester, carboxylic acid or anhydride.Treatment of the o-aminophenol

with cyanogen bromide or chloride or a suitably substituted carbamoylchloride leads to compounds of the invention in which R is amino.Treatment of the o-aminophenol with carbonyl diimidazole gives theoxazolone which leads to compounds of the invention in which R² is halovia treatment with an inorganic anhydride such as phosphoryl chloride orbromide, or to compounds of the invention in which R is alkoxy bytreatment with the appropriate alkylating agent. Replacement of thetosylate with the appropriately substituted azabicycle as above givesthe title compounds of the invention.

Compounds of the invention in which X-Y-Z is N═C(R²)—O, R¹ is hydrogenand R2 is alkyl are most conveniently prepared according to scheme IIIbelow. The appropriate 2′,3′,4′-trihydroxyacylphenone isregioselectively alkylated with glycidyl tosylate or an epihalohydrin inthe presence of a base such as sodium carbonate to give thecorresponding 7-acyl-8-hydroxybenzodioxan-2-methanol. Followingconversion of the ketone to the oxime by reaction with hydroxylaminehydrochloride and sodium acetate, cyclization to the oxazole is effectedby treatment with phosphoryl chloride in the appropriatedimethylalkanoic acid amide. The resulting7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene-8-methanol isconverted to the tosylate by treatment with p-toluenesulfonyl chloridein pyridine and combined with the appropriate azabicycles as describedto give the title compounds of the invention.

2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of Formula I are prepared asdescribed in Scheme IV. Specifically, the allyl side chain of thetosylate is cleaved to the aldehyde by treatment with ozone at lowtemperature, followed by work-up with a tertiary base such asdiisopropylethylamine or triethylamine, or by treatment with catalyticosmium tetroxide and sodium periodate. Reduction of the nitro group withhydrogen over platinum oxide leads directly to formation of the indolein which R² is hydrogen. Alternatively, the aldehyde may be treated withan appropriate alkyl Grignard reagent or with trifluoromethyltrimethylsilane in the presence of cesium fluoride, then oxidized

to a ketone with a suitable oxidant such as pyridinium chlorochromate(PCC) or the Swem reagent and reduced with hydrogen over platinum oxideto give the indoles in which R² is alkyl or trifluoromethyl. Replacementof the tosylate or halide with the appropriately substituted azabicyclein some high boiling solvent such as dimethyl sulfoxide gives the titlecompounds of the invention.

The compounds of the invention in which X-Y-Z is NH—C(R²)═CH and R² is ahalogen such as chlorine or bromine are prepared from the nitroaldehydedescribed by the procedure of Scheme V. The aldehyde is oxidized to thephenylacetic acid by a suitable oxidant such as the Jones reagent (CrO₃,H₂SO₄ in acetone) and then the nitro group is reduced to the amine bytreatment with hydrogen in the presence of a catalyst such as palladiumon carbon. Cyclization to the oxindole is effected by treatment withacid and the oxindole converted to the

haloindole such as bromo or chloroindole via treatment with theappropriate carbon tetrahalide and triphenylphosphine in a solvent suchas methylene chloride. Replacement of the tosylate with theappropriately substituted azabicycle in some high boiling solvent suchas dimethyl sulfoxide gives the title compounds of the invention.

Such compounds of the invention may alternatively be prepared from the7-nitro-8-allyl benzodioxan derived from the Claisen rearrangement bythe procedure of Scheme VI. The alcohol is converted to the tosylate orhalide as described above and the double bond is isomerized by treatmentwith bis-acetonitrile palladium (II) chloride in refluxing methylenechloride or benzene. Cleavage of the olefin with ozone or osmiumtetroxide/periodate gives the o-nitrobenzaldehyde, which is condensedwith the appropriate nitroalkane in the presence of a suitable basecatalyst to yield the corresponding α,β-dinitrostyrene. Reduction ofboth nitro groups with hydrogen over palladium on carbon is accompaniedby cyclization to form the indole. Replacement of the tosylate with theappropriately substituted azbicycle as above, gives the title compoundsof the invention.

Compounds of the invention in which X-Y-Z is NH—C(R²)═CH and R² ismethyl may be most conveniently prepared from the 7-nitro-8-allylbenzodioxan (6) described above by the procedure of Scheme VII. Thenitro group is

reduced with tin (II) chloride dihydrate in refluxing ethyl acetate toproduce and cyclization to the 2-methylindole effected by several days'treatment with catalytic bis-acetonitrile (II) chloride, lithiumchloride and 1,4-benzoquinone at room temperature in tetrahydrofuran.Replacement of the tosylate with the appropriately substitutedazabicycle as above gives the title compounds of the invention

Compounds of the invention where X-Y-Z is N═C(R²)—NH are prepared asillustrated in Scheme VIII below. Specifically, the allyl side chain isisomerized by treatment with catalytic bis-acetonitrile palladium (II)chloride in refluxing methylene chloride or benzene and cleaved to thecorresponding o-nitrobenzaldehyde by treatment with ozone followed bydiisopropylethylamine or by catalytic osmium tetroxide in the presenceof sodium periodate. The aldehyde is oxidized to the o-nitrobenzoic acidby a suitable oxidant such as chromium trioxide (Jones' oxidation) orsodium chlorite and the acid converted to the o-nitroaniline withdiphenylphosphoryl azide (DPPA) in the presence of a

tertiary base such as diisopropylethylamine (Curtius reaction).Reduction of the resulting nitroaniline to the diamine is performed withhydrogen and palladium on carbon and cyclization is achieved bytreatment at reflux with the appropriate carboxylic acid. Refluxing thediamine dihydrochloride in higher boiling carboxylic acids occasionallycauses replacement of a tosylate group with a chloride. Replacement ofthe tosylate or halide with the appropriately substituted azabicycle insome high boiling point solvent such as dimethylsulfoxide give the titlecompound of the invention.

Treatment of the diamine described in Scheme VIII, above, with cyanogenbromide or chloride or a suitably substituted carbamoyl chloride leadsto compounds of the invention in which R² is amino. Treatment of thediamine with carbonyl diimidazole gives the imidazolone which leads tocompounds of the invention in which X-Y-Z is N═C(R²)—NH and R² is halovia treatment with an inorganic anhydride such as phosphoryl chloride orbromide, or to compounds of the invention in which N═C(R²)—NH and R² isalkoxy by treatment with the appropriate alkylating agent. Replacementof the tosylate with the appropriately substituted azabicycle as abovegives the title compounds of the invention.

Compounds of the invention in which N═C(R²)—NH and R² is trifluoromethylmay also be conveniently prepared from the nitroaniline described aboveby the procedure illustrated below in Scheme IX. The nitroaniline istreated with trifluoroacetic anhydride in the presence of a suitabletertiary base such as diisopropylethylamine to yield the o-nitrophenyltrifluoroacetamide. This intermediate is reduced to the o-anilinotrifluoroacetamide by treatment with hydrogen over palladium on carbonand cyclized to the trifluoromethylimidazole in refluxingtrifluoroacetic acid. Replacement of the tosylate with the appropriatelysubstituted azabicycle as above gives the title compounds of theinvention.

The azabicycles appropriate to the invention are known compounds or theymay be prepared by the following procedure. Thus, tropinone is convertedto the corresponding N-benzyltropinone by first reacting with1-chloroethyl chloroformate in hot methylene chloride or1,2-dichloroethane (DCE), treatment of the resulting carbamate with hotmethanol, ethanol or similar alcohols and finally treatment with benzylbromide, benzyl chloride or other benzylating agents known to theskilled artisan in a solvent such as tetrahydrofuran, benzene,N,N-dimethylformamide, or methylene chloride in the presence of atertiary amine base. Benzyltropinone may be converted to the tropinol byreaction with an aryl lithium, aryl Grignard, or other arylorganometallics in a suitable solvent such as tetrahydrofuran or etherat −78° C., followed by warming to room temperature. The arylorganometallics used may be obtained from aryl halides as shown below.Aryl halides may be obtained commercially or by standard routes known tothe skilled artisan. Only the product of exo addition is isolated asshown in the scheme below. The benzyl group may be removed via transferhydrogenation over a precious metal catalyst such as palladium on carbonusing formamide/methanol as the source of hydrogen.

The guaiacols and 2′,3′,4′-trihydroxyacylphenones appropriate to theabove chemistry are known compounds or can be prepared by one schooledin the art. The compounds of the invention may be resolved into theirenantiomers by conventional methods or, preferably, the individualenantiomers may be prepared directly by substitution of(2R)-(−)-glycidyl 3-nitrobenzenesulfonate or tosylate (for the Sbenzodioxan methanamine) or (2S)-(+)-glycidyl 3-nitrobenzenesulfonate ortosylate (for the R enantiomer) in place of epihalohydrin or racemicglycidyl tosylate in the procedures above.

The 5-HT_(1A) affinity of compounds of this invention was established inaccordance with standard pharmaceutically accepted test procedures withrepresentative compounds as follows.

High affinity for the serotonin 5-HT_(1A) receptor was established bytesting the claimed compound's ability to displace [³H] 8-OH-DPAT(dipropylaminotetralin) from the 5-HT_(1A) serotonin receptor followinga modification of the procedure of Hall et al., J. Neurochem. 44, 1685(1985) which utilizes CHO cells stably transfected with human 5-HT_(1A)receptors. The 5-HT_(1A) affinities for the compounds of the inventionare reported below as K_(i)'s.

Antagonist activity at 5-HT_(1A) receptors was established by using a³⁵S-GTPγS binding assay similar to that used by Lazareno and Birdsall(Br. J. Pharmacol. 109: 1120, 1993), in which the test compound'sability to affect the binding of ³⁵S-GTPγS to membranes containingcloned human 5-HT_(1A) receptors was determined. Agonists produce anincrease in binding whereas antagonists produce no increase but ratherreverse the effects of the standard agonist 8-OH-DPAT. The testcompound's maximum inhibitory effect is represented as the L_(max),while its potency is defined by the IC₅₀.

The results of the two standard experimental test procedures describedin the preceding two paragraphs were as follows: 5-HT_(1A) ReceptorAffinity 5-HT_(1A) Function Compound KI (nM) IC₅₀ (nM) (Imax) Example 10.54 53.0 (76%) Example 2 0.77 — Example 3 3.71 27.0 (95%)

The compounds of this invention have potent affinity for and antagonistactivity at brain 5-HT_(1A) serotonin receptors. The compounds of theinvention are thus exceedingly interesting for the treatment ofcognitive dysfunction such as is associated with mild cognitiveimpairment (MCI) Alzheimer's disease and other dementias including LewyBody, vascular, and post stroke dementias. Cognitive dysfunctionassociated with surgical procedures, traumatic brain injury or strokemay also be treated in accordance with the present invention. Further,compounds of the present invention may be useful for the treatment ofdiseases in which cognitive dysfunction is a co-morbidity such as, forexample, Parkinson's disease, autism and attention deficit disorders.

Compounds of the present invention are also useful for treatingcognitive deficits due to CNS disorders such as schizophrenia, (andother psychotic disorders such as paranoia and mano-depressive illness).The compounds are also useful for the treatment of disorders related toexcessive serotonergic stimulation such as anxiety (e.g. generalizedanxiety disorders, panic attacks, and obsessive compulsive disorders),aggression and stress. In addition, compounds of the present inventionmay be useful for the treatment of various physiological conditions suchas Tourette's syndrome, migraine, autism, attention deficit disordersand hyperactivity disorders, sleep disorders, social phobias, pain,thermoregulatory disorders, endocrine disorders, urinary incontinence,vasospasm, stroke, eating disorders such as for example obesity,anorexia and bulimia, sexual dysfunction, and the treatment of alcohol,drug and nicotine withdrawal which are known to be, at least in part,under serotonergic influence. Finally, recent clinical trials employingdrug mixtures (e.g. fluoxetine and pindolol) have demonstrated a morerapid onset of antidepressant efficacy for a treatment combining SSRI(serotonin selective reuptake inhibitor) activity and 5HT1A antagonism(Blier and Bergeron, 1995; F Artigas, et al., 1996, M. B. Tome et al.,1997). The compounds of the invention are thus interesting and useful asaugmentation therapy in the treatment of depressive illness. Compoundsof the present invention may thus be provided in combination with anantidepressant amount of a serotonin selective reuptake inhibitor toincrease the onset of antidepressant efficacy. Such serotonin selectivereuptake inhibitor includes, but is not limited to, fluoxetine,venlafaxine, citalopram, duloxetine, sertraline, paroxetine,fluvoxamine, nefazodone, and mirtazapine, and metabolites thereof.

Thus the present invention provides methods of treating, preventing,inhibiting or alleviating each of the maladies listed above in a mammal,preferably in a human, the methods comprising providing apharmaceutically effective amount of a compound of this invention to themammal in need thereof.

The present invention also provides methods of augmenting the treatmentof depression by providing a mammal, preferably a human, with anantidepressant amount of a serotonin selective reuptake inhibitor (suchas fluoxetine, venlafaxine, citalopram, duloxetine, sertraline,paroxetine, fluvoxamine, nefazodone, and mirtazapine, and metabolitesthereof) and an amount of a compound of Formula I sufficient to hastenthe onset of antidepressant efficacy.

Also encompassed by the present invention are pharmaceuticalcompositions for treating or controlling disease states or conditions ofthe central nervous system comprising at least one compound of FormulaI, mixtures thereof, and or pharmaceutical salts thereof, and apharmaceutically acceptable carrier therefore. Such compositions areprepared in accordance with acceptable pharmaceutical procedures, suchas described in Remingtons Pharmaceutical Sciences, 17th edition, ed.Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985).Pharmaceutically acceptable carriers are those that are compatible withthe other ingredients in the formulation and biologically acceptable.Pharmaceutical compositions of the present invention may furthercomprise a serotonin selective reuptake inhibitor such as, but notlimited to fluoxetine, venlafaxine, citalopram, duloxetine, sertraline,paroxetine, fluvoxamine, nefazodone, and mirtazapine, and metabolitesthereof.

The compounds of this invention may be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets, capsules, powders, solutions, suspensions, emulsions,granules, or suppositories. In such form, the composition is sub-dividedin unit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

The amount provided to a patient will vary depending upon what is beingadministered, the purpose of the administration, such as prophylaxis ortherapy, and the state of the patient, the manner of administration, andthe like. In therapeutic applications, compounds of the presentinvention are provided to a patient already suffering from a disease inan amount sufficient to cure or at least partially ameliorate thesymptoms of the disease and its complications. An amount adequate toaccomplish this is defined as a “therapeutically effective amount.” Thedosage to be used in the treatment of a specific case must besubjectively determined by the attending physician. The variablesinvolved include the specific condition and the size, age and responsepattern of the patient. Generally, a starting dose is about 5 mg per daywith gradual increase in the daily dose to about 150 mg per day, toprovide the desired dosage level in the human.

Provide as used herein means either directly administering a compound orcomposition of the present invention, or administering a prodrug,derivative or analog which will form an equivalent amount of the activecompound or substance within the body.

The present invention includes prodrugs of compounds of Formula I.“Prodrug”, as used herein means a compound which is convertible in vivoby metabolic means (e.g. by hydrolysis) to a compound of Formula t.Various forms of prodrugs are known in the art, for example, asdiscussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985);Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press(1985); Krogsgaard-Larsen, et al., (ed). Design and Application ofProdrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991), Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975).

The following examples illustrate the production of representativecompounds of this invention.

INTERMEDIATE 1 3-Allyloxy-4-methoxynitrobenzene

97.5 g (0.51 mole) of the sodium salt of 5-nitroguaiacol was dissolvedin one liter of DMF and 1.5 equivalents of allyl bromide added. Thereaction was heated to 65° C. for two hours, after which time much ofthe dark color had discharged and tic (1:1 CH2Cl₂/hexane) indicated lossof starting material. The solvent was concentrated in vacuum and theresidue washed with water. The product was isolated by filtration anddried in a vacuum. This gave 112 g of pale yellow solid. A samplerecrystallized from methanol, gave m.p. 93-94° C.

INTERMEDIATE 2 2-Allyloxy-4-nitrophenol

To one liter of dimethyl sulfoxide was added 750 mL of 2 N aqueoussodium hydroxide and the mixture was heated to 65° C. The pale yellowsolid 3-allyloxy-4-methoxynitrobenzene prepared above was added inportions over a 30 minute period and then the temperature was raised to95° C. and maintained for 3 hours, after which time the startingmaterial had been consumed. The mixture was allowed to cool and pouredinto a mixture of 1 L ice and 1 L 2 N HCl. 73 Grams of crude buthomogeneous (by tic 1:1 CH₂Cl₂/hexane) desired product was isolated as alight brown solid by filtration. This material was subsequentlydissolved in 1:1 hexane/methylene chloride and filtered through silicagel to give 68 g of pale yellow solid, which, when recrystallized fromethyl/acetate/hexane, gave m.p. 61-62° C. The aqueous mother liquorsfrom the initial crystallization above were extracted with 2 L of ethylacetate. This was dried over sodium sulfate, filtered and evaporated toa dark oil. Column chromatography on silica with 1:1 CH₂Cl₂/hexane gavean additional 12 g of the title compound as a yellow solid. Elution with2% MeOH in CHCl₃ gave 12 g of a dark oil which slowly crystallized invacuum. This proved to be the Claisen product, 3-allyl4-nitrocatechol.

INTERMEDIATE 3 2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane

20 g (0.50 mole) of 60% NaH/mineral oil was placed in a two liter flaskand washed with 500 mL of hexane. 1 L of DMF was added, followed by 77 g(0.40 mole) of the 2-allyloxy-4-nitrophenol prepared in the previousstep. Addition of the phenol was performed in portions under argon.After stirring the mixture for 30 minutes at room temperature underargon, 108 g (0.48 moles) of (R)-glycidyl tosylate was added. and themixture heated at 70-75° C. under nitrogen overnight. Upon cooling, theDMF was removed in vacuum and replaced with one liter of methylenechloride. This was washed with 500 mL portions of 2 N HCl, saturatedsodium bicarbonate and saturated brine and dried over sodium sulfate.The mixture was filtered, concentrated to an oil in vacuum and columnchromatographed on silica gel using 1:1 hexane/methylene chloride aseluant. This gave 43 g of product contaminated with traces of the twostarting materials, followed by 21 g of pure product as a pale yellowsolid. The impure material was recrystallized from 1.2 L of 10% ethylacetate/hexane to give 34 g of pure (homogeneous on silica gel tic with1:1 hexane/methylene chloride)(R)-2-(2-allyloxy-4-nitrophenoxymethyl)-oxirane (m.p. 64° C.).

Elemental Analysis for: C₁₂H₁₃NO₅ Calc'd: C, 57.37; H, 5.21; N, 5.58Found: C, 57.50; H, 5.21; N, 5.43

INTERMEDIATE 4(8-Allyl-7-nitro-2,3-dihydro-benzo(1.4)dioxin-2-yl)-methanol

(R)-2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane (20 g, 80 mmoles)prepared as above was heated at 155° C. in mesitylene for 24 hours undernitrogen. Filtration of the black solid which formed gave 1.5 g of verypolar material. Evaporation of the solvent in vacuum followed by columnchromatography on silica gel with methylene chloride as eluant gave 10 gof recovered starting material and 7.5 g of the desired rearranged(S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)d ioxin-2-yl)-methanol, whichslowly crystallized on standing in vacuum (m.p. 67° C.). The yield basedon recovered starting material is 75%.

Elemental Analysis for: C₁₂H₁₃NO₅ Calc'd: C, 57.37; H, 5.21; N, 5.58Found: C, 57.26; H, 5.20; N, 5.35

INTERMEDIATE 5 Toluene-4-sulfonic acid8-allyl-7-nitro-2.3-dihydro-benzo(1.4)dioxin-2-ylmethyl ester

9.55 g (38.0 mmole) of(S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol wasdissolved in 465 mL of pyridine, 29.0 g (152 mmole) of p-toluenesulfonylchloride was added and the mixture stirred at room temperature undernitrogen overnight. Water was then added to quench the excess tosylchloride and the solvent was removed in vacuum and replaced withmethylene chloride. This solution was washed with 2 N HCl, withsaturated sodium bicarbonate, and with saturated brine, and dried overmagnesium sulfate. Filtration, evaporation in vacuum and columnchromatography on silica gel with 1:1 hexane/methylene chloride aseluant gave 12.6 g (92%) of toluene4-sulfonic acid(R)-allyl-7-nitro-2,3-benzo(1,4)dioxin-2-ylmethyl ester, which slowlycrystallized to a tan solid (m.p. 60-62° C.) upon standing.

Elemental Analysis for: C₁₉H₁₉NO₇S Calc'd: C, 56.29; H, 4.72; N, 3.45Found: C, 56.13; H, 4.58; N, 3.44

INTERMEDIATE 6{7-Nitro-8-[1-propenyl]-2.3-dihydro-1.4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

To a solution of 10.0 g (24.0 mmole) of(R)-[8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl4-methylbenzenesulfonate in 700 mL of benzene was added 1.03 g ofbis(acetonitrile)dichloropalladium (II) and the mixture was refluxedunder nitrogen for 48 hours. The catalyst was then removed by filtrationand the filtrate concentrated in vacuum to a brown oil. Columnchromatography on silica gel with methylene chloride as eluant gave 7.2g of the title compound as a mixture of E and Z isomers. A sample of{(2R)-7-nitro-8[(E)-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate was obtained as a yellow solid (m.p. 105-106°C.) by evaporation of a pure E isomer-containing fraction.

Elemental Analysis for: C₁₉H₁₉NO₇S Calc'd: C, 56.29; H, 4.72; N, 3.45Found: C, 56.12; H, 4.64; N, 3.39

INTERMEDIATE 7{7-Amino-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

10.0 g (24.0 mmole) of{(2R)-7-nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzo-dioxin-2-yl}methyl4-methylbenzenesulfonate and 28.0 g (123 mmole) of stannous chloridedihydrate were combined and heated to 70° C. in ethyl acetate (250 mL)for 6 hours under nitrogen. After cooling to room temperature, thereaction mixture was poured into ice and was made basic with sodiumbicarbonate. It was then extracted with ethyl acetate, washed withbrine, dried over magnesium sulfate, filtered and evaporated to a brownoil. The crude oil was then chromatographed on silica gel with 50%hexane/methylene chloride to remove impurities and the desired productwas eluted with 0.5% methanol/CH₂Cl₂ to give 8.16 g (91 %) of the(R)-enantiomer of the title compound as a yellow oil. For analyticalpurposes, 50 mg of the yellow oil was crystallized from ethanol with theaddition of fumaric acid to give the fumarate of the title compound. MS(ESI) m/z 375 (M+H)+.

Elemental Analysis for: C₁₉H₂₁NO₅S.1.00 C₄H₄ 0 ₄ Calc'd: C, 56.20; H,5.13; N, 2.85 Found: C, 56.40; H, 4.99; N, 2.91

INTERMEDIATE 8{7{[(Benzyloxy)carbonyl]amino}-8-[1-propenyl]-2.3-dihydro-1.4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

To a solution of{(2R)-7-amino-8-[1-propenyl]-2,3-dihydro-1,4-benzo-dioxin-2-yl}methyl4-methylbenzenesulfonate (4.20 g, 11.2 mmole) in ethyl acetate (150 mL)was added benzyl chloroformate (8.00 mL, 56.0 mmole). The reactionmixture was stirred under nitrogen for 0.5 hour, then a solution ofN,N-diisopropylethylamine (9.75 mL, 56 mmole) in ethyl acetate (75 mL)was added dropwise over a period of 0.5 hour. The mixture was stirred atroom temperature under nitrogen overnight. The reaction was diluted involume to 350 ml and was then washed with 2N HCl (2×100 mL), saturatedsodium bicarbonate (150 mL) and brine (100 mL), dried over magnesiumsulfate, filtered and evaporated to an oil. The crude oil was columnchromatographed on silica gel with 10% ethyl acetate/hexane to removeimpurities and the product eluted with 60% ethyl acetate/hexane to givethe (R)-enantiomer of the title compound as a yellow oil (4.5 g, 79%).¹H (CDCl₃) doublet 7.8 δ(2 ); multiplet 7.4 δ(7 H); doublet 6.7 δ(2 H);multiplet 6.0-6.2 δ(2 H); singlet 5.2 δ(2 H); multiplet 4.4 δ(1 H);multiplet 4.2 δ(3H); multiplet 4.0 δ(1 H); singlet 2.4 δ(3 H); doublet1.9 δ(3 H).

INTERMEDIATE 9{7{[(Benzyloxy)carbonyl]amino}-8-formyl-2.3-dihydro-1.4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

To a solution{(2R)-7-{[(benzyloxy)carbonyl]amino}-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate (4.5 g, 8.84 mmole) in tetrahydrofuran (225 mL)was added OsO₄ (1.65 mL, 0.270 mmole). Then a solution of NalO₄ (9.45 g,44.2 mmole) in water (100 mL) was added dropwise. The reaction wasstirred at room temperature under nitrogen overnight. Water (250 mL) wasadded to the mixture and it was then extracted with ethyl acetate. Theorganic phase was then washed with brine, dried over magnesium sulfate,filtered and evaporated to 4.45 g (>95%) of the (R)-enantiomer of thetitle compound as a yellow solid. ¹H (CDCl₃) broad singlet 10.8 δ(1 H);singlet 10.1 δ(1 H); doublet 7.9 δ(1 H); doublet 7.8 δ(2 H); multiplet7.4 δ(7 H); doublet 7.0 δ(1 H); singlet 5.2 8 (2 H); multiplet 4.5 δ(1H); multiplet 4.2 δ(3 H); multiplet 4.1 δ(1 H); singlet 2.4 δ(3 H).

INTERMEDIATE 10{7-{[(Benzyloxy)carbonyl]amino}-8-hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

A solution of{(2R)-7-{[(benzyloxy)carbonyl]amino}-8-formyl-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate (4.45 g, 8.95 mmole) in methylene chloride (50mL) was added dropwise to a solution of m-chloroperoxybenzoic acid (6.459, 22.4 mmole) in methylene chloride (120 mL). The reaction was stirredunder nitrogen overnight. After dilution to 300 mL in volume, it waswashed with saturated sodium bicarbonate (2×200 mL), brine (100 mL),dried over magnesium sulfate, filtered and evaporated to dryness. A H¹NMR spectra was taken of the crude product and it was determined to bethe formate ester. Cleavage was effected by stirring in methanol overbasic alumina overnight. After filtration and evaporation, the productwas purified by column chromatography on silica gel with hexane toremove the impurities, and the product eluted with methylene chloride togive the (R)-enantiomer of the title compound as a yellow oil (1.80 g,40%). ¹H (CDCl₃) doublet 7.8 δ(2 H); multiplet 7.2-7.4 δ(7 H); broadsinglet 7.0 δ(1 H); doublet 6.4 δ(1 H); singlet 5.2 δ(2 H); multiplet4.4 δ(1 H); multiplet 4.2 δ(3 H); multiplet 4.0 δ(1 H); singlet 2.4 6 (3H).

INTERMEDIATE 11{7-Amino-8-hydroxy-2.3dihydro-1.4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

A mixture of(2R)-7-{[(benzyloxy)carbonyl]amino}-8-hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate (1.8 g, 3.7 mmole), 2.0 ml of 4.0 Nisopropanolic HCl, and 0.25 q of 10% palladium on carbon in 200 mL ofmethanol was treated with 40 psi of hydrogen on a Parr shaker for 3hours. The catalyst was filtered and washed with additional methanol.The solvent was evaporated in vacuum to yield 1.25 g (87%) of the(R)-enantiomer of the hydrochloride hemihydrate of the title compound asa beige foam.

Elemental Analysis for: C₁₆H₁₇NO₆S.1.00 HCl.0.5 H₂O Calc'd: C, 48.43; H,4.83; N, 3.53 Found: C, 48.21; H, 4.34; N, 3.58

INTERMEDIATE 12 7.8-Dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl4-methylbenzenesulfonate

[(2R)-7-Amino-8-hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl]methyl4-methyl-benzenesulfonate hydrochloride (1.05 g, 2.99 mmole) intrimethyl orthoformate (7 mL) was heated to reflux in the presence of0.20 g of p-toluenesulfonic acid for 3 hours. The solvent was removedunder high vacuum to yield a beige solid. The crude product wasrecrystallized from ethanol to give 0.81 g (75%) of the (R)-enantiomerof the title compound, MS (ESI) m/z 361 (M+H)+.

Elemental Analysis for: C₁₇H₁₅NO₅S Calc'd: C, 56.50; H, 4.18; N, 3.88Found: C,56.10; H, 4.37; N, 3.69

INTERMEDIATE 131-[5-Hydroxy-3-(hydroxymethyl)-2.3-dihydro-1.4-benzodioxin-6-yl]-1-ethanone

To a solution of 2′,3′,4′-trihydroxyacetophenone (10.6 g, 63.0 mmole) inDMF (75 mL) was added potassium carbonate (17.4 g, 126 mmole). After 5minutes (R)-glycidyl tosylate (9.67 g, 42.3 mmole) was added, then theheterogeneous mixture was heated to 70° C. for 3 hours. After removal ofthe solvent in vacuum, the residue was taken into water (800 mL) and wasthen extracted with ethyl acetate (4×300 mL). The combined organiclayers were dried over magnesium sulfate, filtered and evaporate todryness in vacuum. The crude brown oil thus obtained was columnchromatographed on silica gel with 40% hexane/ethyl acetate as eluant togive the (S)-enantiomer of the title compound as a yellow oil whichsolidifies upon standing (7.5 g, 78%). MS (ESI) m/z 223 (M−H)−.

Elemental Analysis for: C₁₁H₁₂O_(5.)0.10 H₂O Calc'd: C, 58.46; H, 5.44Found: C, 58.02; H, 5.09

INTERMEDIATE 141-[5-Hydroxy-3-(hydroxymethyl)-2.3-dihydro-1.4-benzodioxin-6-yl]-1-ethanoneoxime

A solution of hydroxylamine hydrochloride (2.38 g, 34.2 mmole) in 1:1ethanol/pyridine (100 mL) was added to a solution of1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone(1.92 g, 8.57 mmole) in ethanol (200 mL). It was then heated to refluxunder nitrogen for 5 hours. Upon cooling, the solvent was removed andreplaced with ethyl acetate. The solution was then washed with water(200 mL) and with aqueous 2N HCl (100 mL), dried over magnesium sulfate,filtered and evaporated in vacuum to give 1.89 g (93%) of the(S)-enantiomer of the title compound as a gray solid, m.p. 162° C. MS(ESI) m/z 240 (M+H)+.

Elemental Analysis for: C₁₁H₁₃NO_(5.)0.35 H₂O Calc'd: C, 53.81; H, 5.62;N, 5.71 Found: C, 53.51; H, 5.30; N, 5.58

INTERMEDIATE 15[2-Methyl-7.8dihydro[1.4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methanol

3.03 9 (12.6 mmole) of 1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanoneoxime was dissolved in a mixture of 1:3N,N-dimethylacetamide/acetonitrile (100 mL). The solution was cooled inan ice/water bath and a solution of phosphorus oxychloride (1.26 mL, 35mmole) in 1:3 N,N-dimethylacetamide/acetonitrile (30 mL) was added. Thereaction mixture was stirred under nitrogen over a period of 48 hours.It was then added to an ice cold, saturated solution of sodium acetate,extracted with ethyl acetate, dried over magnesium sulfate, filtered andevaporated in vacuum. The resulting crude oil was column chromatographedon silica gel with 60% hexane/ethyl acetate to remove impurities and theproduct eluted with 40% hexane/ethyl acetate. After evaporation of thesolvent in vacuum, 2.08 g (75%) of the (S)-enantiomer of the titlecompound was obtained as a white solid, m.p. 120° C. MS (ESI) m/z 222(M+H)+.

Elemental Analysis for: C₁₁H₁₁NO_(4.)0.20 H₂O Calc'd: C, 58.77; H, 5.11;N, 6.23 Found: C, 58.93; H, 4.91; N, 6.14

INTERMEDIATE 16[2-Methyl-7.8-dihydro[1,4]dioxino[2.3-g][1.3]benzoxazol-8-yl]methyl4-methylbenzenesulfonate

To a solution of[(8S)-2-methyl-7,8-dihydro[1,4]dioxino[2,3-g]-[1,3]benzoxazol-8-yl]methanol(1.80 9, 8.14 mmole) in methylene chloride (100 mL) was addedp-toluenesulfonyl chloride (3.90 g, 20.4 mmole). The mixture was cooledin an ice bath and a solution of diisopropylethylamine ( 3.55 mL, 20.4mmole) in methylene chloride (20 mL) was then added dropwise, followedby 4-dimethyl-aminopyridine (0.65 g, 5.30 mmole). The solution wasallowed to warm to room temperature and was stirred under nitrogenovernight. The reaction was diluted to 500 mL in volume with methylenechloride, then washed with aqueous 2 N HCl (200 mL), with saturatedaqueous sodium bicarbonate (200 mL), and with brine (150 mL), dried overmagnesium sulfate, filtered and evaporated in vacuum to a yellow oil.The crude oil was column chromatographed on silica gel using methylenechloride to remove impurities and 3% methanol/methylene chloride toelute the (R)-enantiomer of the title compound, which becomes a whitesolid under vacuum (2.56 9, 84%), m.p. 123° C. MS (ESI) m/z 376 (M+H)+.

Elemental Analysis for: C₁₈H₁₇NO₆S.0.20 H₂O Calc'd: C, 57.04; H, 4.63;N, 3.70 Found: C, 56.75; H, 4.62; N, 3.51

EXAMPLE 18-{[2-Methyl-7.8-dihydro[1,4]dioxino[2,3-g][1.3]benzoxazol-8-yl]methyl}-3-phenyl-8-azabicyclo[3.2.]octan-3-ol

(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl4-methylbenzenesulfonate (0.375 g, 1.00 mmole) and3-phenyl-8-aza-bicyclo[3.2.1]-octan-3-ol (0.25 g, 1.2 mmole) werecombined in 8 mL of DMSO. This solution was heated to 75-80° C. undernitrogen for 8 hours. After completion, the reaction was cooled to roomtemperature and diluted to 500 mL with ethyl acetate. The mixture waswashed twice with 400 mL portions of saturated aqueous sodiumbicarbonate, with 300 mL of water and twice with 400 mL of saturatedbrine, dried over sodium sulfate, filtered and concentrated in vacuum.The crude oil was column chromatographed on silica gel using firstmethylene chloride to remove impurities and then 0.5% methanol/methylenechloride to give, after concentration of the product fractions invacuum, 0.12 g of the (S)-enantiomer of the title compound as anoff-white solid, m.p. 203-205° C.

Elemental Analysis for: C₂₄H₂₆N₂O_(4.)0.10 CH₂Cl₂ Calc'd: C, 69.76; H,6.36; N, 6.75 Found: C, 69.83; H, 6.52; N, 6.77

EXAMPLE 28-{[2-Methyl-7.8-dihydro[1,4]dioxino[2.3-g][1,3]benzoxazol-8-yl]methyl}-3-[3-(trifluoromethyl)phenyl]-8-azabicyclo[3.2.]octan-3-ol

(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl4-methylbenzenesulfonate (0.40 g, 1.1 mmole) and3-(3-trifluoromethyl-phenyl)-8-aza-bicyclo [3.2.1]octan-3-ol (0.50 g,1.8 mmole) were combined in 8 mL of DMSO. This solution was heated at82° C. under nitrogen for 6 hours. After completion, the reaction wascooled to room temperature and diluted to 500 mL with ethyl acetate. Themixture was washed twice with 400 mL portions of saturated aqueoussodium bicarbonate, with 300 mL of water and twice with 400 mL ofsaturated brine, dried over sodium sulfate, filtered and concentrated invacuum to give 0.52 g of a brown oil. The crude oil was columnchromatographed on silica gel using first methylene chloride to removeimpurities and then 0.8% methanol/methylene chloride to give, afterconcentration of the product fractions in vacuum, 0.23 g of the(S)-enantiomer of the title compound as a white solid, m.p. 148-150° C.

Elemental Analysis for: C₂₅H₂₅F₃N₂O₄ Calc'd: C, 63.29; H, 5.31; N, 5.90Found: C, 63.29; H, 5.26; N, 5.72

INTERMEDIATE 17 8-Benzyl-8-aza-bicyclo[3.2.1]octan-3-one

To a stirred solution of 29.2 g (209 mmole) tropinone in 300 mL of1,2-dichloroethane was added 45.5 mL (419 mmole) 1-chloroethylchloroformate, and the resulting solution was warmed to 80° C. Thereaction was monitored by thin layer chromatography on a silica gelplate eluting with EtOAc/2M NH₃:MeOH (5:1). After stirring for 18 h, thesolvent was evaporated, 300 mL MeOH was added, and the reaction washeated to reflux. After 45 min, the solvent was evaporated, then 300 mLTHF, 38.83 g (227 mmol) benzyl bromide, and 33 mL (24.0 9, 237 mmol)triethylamine was added, and the resulting mixture was stirred at 23° C.

After 69 h, the mixture was transferred to a separatory funnelcontaining 200 mL sat. NaHCO₃ solution. The aqueous layer was extractedwith EtOAc (2×300 mL), then the combined organics were washed with water(100 mL), brine (100 mL), dried over MgSO₄ filtered and evaporated to abrown oil. The crude material was purified by flash chromatography onSiO₂, using a gradient elution of CH₂Cl₂/EtOAc (40:1 to 20:1 to 8:1 to4:1). The appropriate fractions were combined and evaporated to afford19.91 g (92 mmol, a 44% yield) of the title compound as a yellow-orangeoil. MS (ES) m/z. 216 (MH)⁺.

INTERMEDIATE 188-Benzyl-3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol

To a −78° C. solution of 10.75 g (50.35 mmol) 2-bromonaphthalene in 200mL THF was added 20.1 mL (50.25 mmol) of n-BuLi (2.5 M in hexanes) indrops over 5 min. After 35 min, a solution of 10.51 g (48.82 mmol)8-benzyl-8-aza- bicyclo[3.2.1]octan-3-one in 25 mL THF was added viacannula, and then allowed to warm to room temperature. After 17 h, themixture was transferred to a separatory funnel containing 200 mL brine.The aqueous layer was extracted with EtOAc (3×150 mL), then the combinedorganics were washed with water (100 mL), brine (100 mL), dried overMgSO₄, filtered and evaporated to an orange oil.

The crude material was purified by flash chromatography on SiO₂, using agradient elution of CH₂Cl₂/EtOAc (40:1 to 20:1 to 8:1 to 4:1 to 2:1 to1:1). The appropriate fractions were combined and evaporated to afford7.07 g (20.6 mmol, a 42% yield) of the title compound as a yellow oil.MS (ES) m/z: 345 (MH)+.

INTERMEDIATE 19 3-Naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol

To 3.80 g (11.1 mmol)8-benzyl-3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol was added 1.20g (19.0 mmol) of ammonium formate, 100 mL MeOH, and 2.46 g Pd/C (10 wt.%). The reaction mixture was heated to 50° C., and was monitored by TLCon a SiO₂ plate with CHCl₃:MeOH (10:1). After 21 h, the mixture wascooled to room temperature, filtered through a pad of celite andevaporated to afford 2.0 g (7.9 mmol, a 72% yield) of the title compoundas an off-white solid. MS (ES) m/z: 344 (MH)⁺.

EXAMPLE 38-{[2-Methyl-7.8-dihydro[1.4]dioxino[2.3-g][1.3]benzoxazol-8-yl]methyl}-3-(2-naphthyl)-8-azabicyclo[3.2.1]octan-3-ol

(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl4-methylbenzenesulfonate (0.40 g, 1.1 mmole) and3-(2-naphthyl)-8-aza-bicyclo-[3.2.1]octan-3-ol (0.35 g, 1.4 mmole) werecombined in 6.5 mL of DMSO. This solution was heated at 80° C. undernitrogen for 14 hours. After completion, the reaction was cooled to roomtemperature and diluted to 500 mL with ethyl acetate. The mixture waswashed twice with 400 mL portions of saturated aqueous sodiumbicarbonate, with 300 mL of water and twice with 400 mL of saturatedbrine, dried over sodium sulfate, filtered and concentrated in vacuum togive 0.43 g of a brown oil. The crude oil was column chromatographed onsilica gel using first methylene chloride to remove impurities and then0.8% methanol/methylene chloride to give, after concentration of theproduct fractions in vacuum, 0.12 g of the (S)-enantiomer of the titlecompound as an off-white solid, m.p. 192-195° C.

Elemental Analysis for: C₂₄H₂₆N₂.O₄.0.20 CH₂Cl₂ Calc'd: C, 71.53; H.6.05; N, 5.92 Found: C, 71.53; H, 6.19; N. 5.92

1-15. (canceled)
 16. A method of treating a subject suffering from acondition selected from the group consisting of cognitive dysfunction,neurodegenerative disease, and schizophrenia which comprises providingto the subject suffering from said condition, a therapeuticallyeffective amount of a compound of formula I

wherein R¹ is hydrogen, halo, cyano, carboxamido, carboalkoxy of two tosix carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono-or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms; X-Y-Z is N═C(R²), N═C(R²)—NH or NH—C(R²)═CH; R² is hydrogen,halo, trifluoromethyl, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkoxy of one to six carbon atoms oralkyl of one to six carbon atoms; and R³ is phenyl, naphthyl, anthracyl,phenanthryl, pyridyl, pyrimidyl, triazinyl, thienyl, furyl, pyrrolyl,pyrazolyl, indolyl, imidazolyl, benzofuryl, benzothienyl, oxazolyl, orthiazolyl, each optionally substituted with from one to threesubstituents selected from the group consisting of hydroxy, halo,trifluoromethyl, cyano, amino, mono- or di-alkylamino in which eachalkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atomsand alkyl of one to six carbon atoms; or a pharmaceutically acceptablesalt thereof.
 17. The method of claim 16 wherein the subject is a human.18. A method of treating a subject suffering from a condition selectedfrom the group consisting of anxiety, aggression and stress whichcomprises providing to the subject suffering from said condition, atherapeutically effective amount of a compound of formula I

wherein R¹ is hydrogen, halo, cyano, carboxamido, carboalkoxy of two tosix carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono-or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms; X-Y-Z is N═C(R²), N═C(R²)—NH or NH—C(R²)═CH; R² is hydrogen,halo, trifluoromethyl, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkoxy of one to six carbon atoms oralkyl of one to six carbon atoms; and R³ is phenyl, naphthyl, anthracyl,phenanthryl, pyridyl, pyrimidyl, triazinyl, thienyl, furyl, pyrrolyl,pyrazolyl, indolyl, imidazolyl, benzofuryl, benzothienyl, oxazolyl, orthiazolyl, each optionally substituted with from one to threesubstituents selected from the group consisting of hydroxy, halo,trifluoromethyl, cyano, amino, mono- or di-alkylamino in which eachalkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atomsand alkyl of one to six carbon atoms; or a pharmaceutically acceptablesalt thereof.
 19. The method of claim 18 wherein the subject is a human.20. A method of treating a subject suffering from a condition selectedfrom the group consisting of eating disorders, disorders ofthermoregulation, sleep dysfunction and sexual dysfunction whichcomprises providing to the subject suffering from said condition, atherapeutically effective amount of a compound of formula I

wherein R¹ is hydrogen, halo, cyano, carboxamido, carboalkoxy of two tosix carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono-or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms; X-Y-Z is N═C(R²), N═C(R²)—NH or NH—C(R²)═CH; R² is hydrogen,halo, trifluoromethyl, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkoxy of one to six carbon atoms oralkyl of one to six carbon atoms; and R³ is phenyl, naphthyl, anthracyl,phenanthryl, pyridyl, pyrimidyl, triazinyl, thienyl, furyl, pyrrolyl,pyrazolyl, indolyl, imidazolyl, benzofuryl, benzothienyl, oxazolyl, orthiazolyl, each optionally substituted with from one to threesubstituents selected from the group consisting of hydroxy, halo,trifluoromethyl, cyano, amino, mono- or di-alkylamino in which eachalkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atomsand alkyl of one to six carbon atoms; or a pharmaceutically acceptablesalt thereof.
 21. The method of claim 20 wherein the subject is a human.22. A method of treating a subject suffering depression comprisingproviding to the subject suffering from said condition, anantidepressant amount of a serotonin selective reuptake inhibitor and anamount of a compound of formula I

wherein R¹ is hydrogen, halo, cyano, carboxamido, carboalkoxy of two tosix carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono-or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbonatoms; X-Y-Z is N═C(R²), N═C(R²)—NH or NH—C(R²)═CH; R² is hydrogen,halo, trifluoromethyl, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkoxy of one to six carbon atoms oralkyl of one to six carbon atoms; and R³ is phenyl, naphthyl, anthracyl,phenanthryl, pyridyl, pyrimidyl, triazinyl, thienyl, furyl, pyrrolyl,pyrazolyl, indolyl, imidazolyl, benzofuryl, benzothienyl, oxazolyl, orthiazolyl, each optionally substituted with from one to threesubstituents selected from the group consisting of hydroxy, halo,trifluoromethyl, cyano, amino, mono- or di-alkylamino in which eachalkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atomsand alkyl of one to six carbon atoms; or a pharmaceutically acceptablesalt thereof; said amount being effective to increase the onset ofantidepressant efficacy.
 23. The method of claim 22 wherein the subjectis a human.
 24. The method of claim 22 wherein the serotonin selectivereuptake inhibitor is fluoxetine, venlafaxine, duloxetine, sertraline,paroxetine, fluvoxamine, nefazodone, or mirtazapine. 25-26. (canceled)27. The method of claim 16 wherein said condition is cognitivedysfunction.
 28. The method of claim 16 wherein said condition isneurodegenerative disease.
 29. The method of claim 16 wherein saidcondition is schizophrenia.
 30. The method of claim 18 wherein saidcondition is anxiety.
 31. The method of claim 18 wherein said conditionis aggression.
 32. The method of claim 18 wherein said condition isstress.
 33. The method of claim 20 wherein said condition is an eatingdisorder.
 34. The method of claim 20 wherein said condition is adisorder of thermoregulation.
 35. The method of claim 20 wherein saidcondition is sleep dysfunction.
 36. The method of claim 20 wherein saidcondition is sexual dysfunction.
 37. A method comprising contacting a5HT_(1A) receptor with a compound of claim 1.